The methods of delivery of pharmaceuticals orally in recent years has undergone significant changes. In the past, orally administered pharmaceuticals were manufactured in tablet form and more recently in a capsule form containing powders. The capsules were made generally of gelatin which generally is a water-soluble polyamide containing compound.
One of the recent changes has been an increase in the size of the tablet to be delivered orally. Another has been an interest by manufacturer, distributor, and user to assure that the vesicular sections of a gelatin capsule may not be separated to tamper with or adulterate the pharmaceutical contained in the capsule. Even more recently, to avoid issues of tampering with powders in capsules, pharmaceutical manufacturers have introduced tablets in the shape of capsules, also called caplets. These caplets may be encased in gelatin capsules, the combination sometimes called gelcaps.
Commonly, the vesicular sections of a gelatin capsule are molded to provide a force fit as one section is pressed inside the other section to form the capsule. Unfortunately, this force fit has not prevented tampering with the pharmaceutical contained in the capsule. Such malevolent tampering has caused loss of life, personal injury, withdrawal of otherwise salutary pharmaceutical products from the marketplace, and damage to the goodwill and reputation of the pharmaceutical manufacturers making and distributing otherwise salutary products.
Previous methods tried to seal gelatin capsules have been inadequate for one reason or another.
Heat has been applied to seal gelatin capsules after filling. U.S. Pat. No. 4,820,364 (Graham) discloses an "adhesion promoting fluid" such as a lower alkanol having a high dielectric constant being applied to the overlapping capsule walls and dielectric thermal energy is employed to cause local heating and sealing. In a related approach, U.S. Pat. No. 4,756,902 (Harvey et al.) discloses an alcohol/water mixture which is used as a "sealing fluid" and is applied to the overlapping section of the cap and base of the capsule. Heat may be used and a gelatin band outside the two halves of the capsule is additionally used for further sealing.
Humidity has been used as the means of bringing about capsule sealing by introducing steam briefly as the capsule is closed. See, for example, U.S. Pat. No. 4,522,666 (Wittwer). Canadian Patent No. 1,198,381, also discloses sealing by exposure to steam or hot water.
Mechanical approaches to seal capsules have been described. U.S. Pat. No. 4,534,467 (Rathbun) discloses the use of interlocking sawtooth formations on the cap interior and base exterior. U.S. Pat. No. 4,677,812 (Tayebi) and U.S. Pat. No. 4,866,906 (Tayebi) disclose the use of an indented embossed groove system to make a mechanical seal which is augmented by the use of heat to fuse the indentation. European Patent Publication No. 0 271 292 (Ansell) discloses a capsule design such that the base fits into the cap in a way that there is little or no base protruding from the cap for a tamperer to grip to open a capsule. U.S. Pat. No. 4,478,658 (Wittwer) discloses applying a frangible, edible label to cover a portion of the capsule seam on the outside of the capsule.
Sealing of gelatin capsules using various sealing materials and methods has also been described.
Sealing of the entire band or seam between the capsule halves is one approach, especially when a liquid is to be encased in the capsule.
Japanese Patent Publication No. 72050367 discloses the use of an organic solvent solution of either polyvinyl acetal diethylaminoacetate or hydroxypropylcellulose applied as a coating bandwise around the capsule using a capsule banding machine. Additives to the solvent solution to increase adhesiveness include modified cellulose materials and polyvinyl pyrrolidone.
U.S. Pat. No. 4,443,461 (Goustard et al.) discloses a mechanically elaborate capsule capping system to provide a liquid-tight seal of a hard gelatin capsule enclosing freely-flowing liquids or powders by placing a bead of viscous adhesive about the interior of the capsule cap before fitting the cap over the liquid filled base. The viscous adhesive is preferably a solution of gelatin or polyvinyl pyrrolidone in water or in a mixture of alcohol and water.
U.S. Pat. No. 4,581,875 (MacLaughlin) discloses methods of "tackifying" the overlap area of gelatin capsule base and cap by use of a thin line steam jet or impinging with atomized gelatin solution in water followed by rotating at least one half to homogenize the tackification area and fuse the halves together.
European Patent Publication No. 0 110 603 discloses the use of droplets of sealing fluid at high frequency from a jet, deposited between the overlapping regions of the cap and base for a complete seal to contain liquids and uses various means to assure that the sealing fluid (cyanoacrylate monomer, polyvinyl alcohol solution, aqueous polyvinyl pyrrolidone solution, or nitrocellulose in acetone, ethyl acetate, or methyl acetate) is distributed or deposited continuously along a seam defined by the overlapping regions.
Another chemical approach has been to modify the capsule's integrity at the point of joining the capsule sections.
Canadian Patent 1,198,381 in addition to designing capsules so that closing does not present a grippable capsule base protruding from the cap, also discloses the use of a polymer solution or emulsion containing a "softener" to seal the body to the cap. U.S. Pat. No. 4,539,060 (Wittwer) discloses the sealing of capsules by evenly distributing a sealing fluid between the overlap of the cap and body side walls of the gelatin capsule by capillary effect. The sealing fluid dissolves the amorphous part of the gelatin between the overlap.
Yet another approach has been to encase or substantially cover the filled capsule with another material. An English language abstract of German Patent No. 1767032 discloses sealing of capsules by dipping the complete capsule in a solution in an organic solvent of a natural or synthetic "binding agent", e.g., acrylic resins, polyvinyl acetates, polyvinyl pyrrolidone, cellulose acetate phthalate, cellulose ethers, alginates, etc. Japanese Patent Publication No. 65015667 discloses sealing capsules with a gel drug in the capsule base by closing with a cap which was soaked in an alcoholic solution of polyvinylpyrrolidone before closing the capsule. U.S. Pat. No. 4,844,906 (Hermelin) discloses a capsule whose outside surface has been at least 66% covered by a tamper evident coating.
Yet another approach has been to adhesively bind each end of a caplet to the internal surfaces of the capsule with no sealing of the capsule sections at the point of overlap. U.S. Pat. No. 4,928,840 (Barshay et al.) discloses the use of an edible adhesive, including protein adhesives, a plastic adhesive, shellac or a cellulose soluble in water or an organic solvent to adhere the opposite ends of a caplet to the inside surfaces of the capsule ends. The gelatin is described as a semi-permeable membrane.
Methods employing heat, humidity or fluids which weaken the gelatin capsule are inadequate because such methods could adversely affect the integrity of the gelatin comprising the capsule or the integrity or pharmacology of the pharmaceutical inside the capsule.
Mechanical methods to attempt sealing are inadequate because such methods are complex for commercial scale manufacturing and may not thwart a tamperer who can remove the sections and restore them in the same or similar manner as those sections were originally joined.
Coating methods to encase or substantially cover the filled capsule are inadequate because of the impracticality of handling such capsules during commercial production. Coatings, many of which are water insoluble can interfere with the dissolution of the gelatin and the therapeutic release of the pharmaceutical.
Further, when a pharmaceutical caplet is encased in a gelatin capsule, to form a gelcap, the caplet dimensions are smaller than the capsule, permitting the caplet to move about within the capsule. Because the caplet density is invariably higher than the capsule density, the mobility of the caplet within the capsule can damage the capsule or otherwise provide an unsettling sound and feeling as the user takes the gelcap orally.
What is needed for the art of gelatin capsule assembly is a sealant and a method for sealing capsules which will effectively seal the two sections of the gelatin capsule together with minimal processing changes to conventional gelatin capsule assembly but without altering the appearance or performance of the gelatin capsule or the pharmacology of the pharmaceutical, in order to minimize tampering, and desirably also to immobilize a caplet within a capsule.